U.S. patent number 3,853,903 [Application Number 05/374,854] was granted by the patent office on 1974-12-10 for substituted 2 -benzoylisoxazolidines.
This patent grant is currently assigned to Gruppo Lepetit S.p.A.. Invention is credited to Amedeo Omodei Sale.
United States Patent |
3,853,903 |
Sale |
December 10, 1974 |
**Please see images for:
( Certificate of Correction ) ** |
SUBSTITUTED 2 -BENZOYLISOXAZOLIDINES
Abstract
2-Benzoylisoxazolidines of the formula Wherein R and R.sub.1
each independently represents lower alkyl, carbo-lower alkoxy or
phenyl or one of which additionally is hydrogen, and R.sub.2
represents lower alkyl or lower acyl. The compounds of the
invention have central nervous system (CNS) activity, essentially
characterized by long-lasting hypnotic, sedative and myorelaxing
effects. The compounds also display a strong anxiety relieving
effect.
Inventors: |
Sale; Amedeo Omodei (Voghera,
IT) |
Assignee: |
Gruppo Lepetit S.p.A. (Milan,
IT)
|
Family
ID: |
11223213 |
Appl.
No.: |
05/374,854 |
Filed: |
June 29, 1973 |
Foreign Application Priority Data
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|
|
|
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Aug 17, 1972 [IT] |
|
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28245/72 |
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Current U.S.
Class: |
548/240 |
Current CPC
Class: |
C07D
261/02 (20130101) |
Current International
Class: |
C07D
261/00 (20060101); C07D 261/02 (20060101); C07d
085/08 () |
Field of
Search: |
;260/37FA |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Pifferi et al., J. Med. Chem., 1972, 15(8), 851-853..
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Primary Examiner: Rush; Raymond V.
Attorney, Agent or Firm: Post; Theodore Bjork; C.
Kenneth
Claims
What I claim is:
1. A 2-benzoyl-isoxazolidine which is
2-(4-acetoxy-3,5-dimethoxybenzoyl)-5-carbomethoxy-5-methyl-isoxazolidine,
5-phenyl-2-(3,4,5-trimethoxybenzoyl)-isoxazolidine, or
3-phenyl-2-(3,4,5-trimethoxybenzoyl)-isoxazolidine.
2. The compound of claim 1 which is
2-(4-acetoxy-3,5-dimethoxybenzoyl)-5-carbomethoxy-5-methyl-isoxazolidine.
3. The compound of claim 1 which is
5-phenyl-2-(3,4,5-trimethoxybenzoyl)-isoxazolidine.
4. The compound of claim 1 which is
3-phenyl-2-(3,4,5-trimethoxybenzoyl)-isoxazolidine.
Description
BACKGROUND OF THE INVENTION
Substituted 2-benzoyl- and 2-cinnamoyl-isoxazolidines of the
formula ##SPC1##
Wherein n is zero or one, and R.sub.1, R.sub.2 and R.sub.3
independently are hydrogen, hydroxy, a 1 to 3 carbon alkoxy or an
acetoxy group, wherein no more than one of such groups is hydrogen
are known; U.S. Pat. No. 3,696,096. These compounds differ from
those herein claimed in that they have no substitution on the
isoxazolidine ring. The known compounds do not have long-lasting
hypnotic, sedative and myorelaxing activity, unlike the compounds
herein claimed.
SUMMARY OF THE INVENTION
This invention is concerned with substituted
2-benzoylisoxazolidines corresponding to the formula ##SPC2##
Wherein R and R.sub.1 each independently represents lower alkyl,
carbo-lower alkoxy or phenyl, or one of which additionally
represents hydrogen, and R.sub.2 represents lower alkyl or lower
acyl. Compounds wherein neither R nor R.sub.1 represents hydrogen
form a sub-group of the novel compounds. As used in the
specification and claims, the terms "lower alkyl" and "lower acyl"
designate respectively, alkyl and acyl moieties containing from 1,
to 2, to 3, to 4, to 5, to 6 carbon atoms such as methyl, ethyl,
propyl, butyl, pentyl, hexyl; and formyl, acetyl, propionyl,
butyryl, pentanoyl and hexanoyl, respectively. The term "lower
alkoxy" represents an alkoxy group containing from 1, to 2, to 3,
to 4, to 5 carbon atoms such as methoxy, ethoxy, propoxy, butoxy
and pentoxy.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following exemplary details further describe the invention and
the manner and process of making and using it to enable the art
skilled to make and use the same and set forth the best mode
contemplated by the inventor of carrying out the invention.
The compounds of the invention are prepared by contacting an
isoxazolidine of the formula ##SPC3##
Wherein R and R.sub.1 have the above meaning, either as free base
or in the form of its mineral acid addition salt, with a
substituted benzoyl halide of the formula ##SPC4##
Wherein R.sub.2 has the significance given before and hal
represents a halo group, in the presence of a hydrogen chloride
acceptor, advantageously selected from (a) the tertiary aliphatic
amines, such as trimethyl amine or triethyl amine, (b) pyridine or
(c) the picolines.
The reaction is carried out in an inert organic solvent, such as a
lower alkyl halogenated hydrocarbon, tetrahydrofuan and the like,
of which methylene chloride is preferred, at a temperature varying
from about 0.degree.C. to the boiling temperature of the solvent,
and preferably at room temperature as the lower limit. The reaction
time ranges from about 2 to about 6 hours and best results are
obtained when the reaction is completed within about 3 to about 5
hours. Although the amounts of the reactants are not critical, it
is advantageous to use substantially equimolecular proportions of
the isoxazolidine derivative and of the benzoyl chloride, whereas
the organic nitrogen base acid acceptor is generally employed in
the ratio 1.1-1.5 mole for each equivalent of the total acid
present at the end of the reaction.
The end products are recovered from the reaction mixture by known
procedures and are purified by usual techniques, for example by
recrystallization from a suitable solvent, by distillation or by
chromatography.
The starting isoxazolidine compounds are prepared as described in
the examples, and the benzoyl chlorides are prepared from the
corresponding acids pursuant to well-known procedures.
The following non-limitative examples describe in detail compounds
illustrative of the present invention and methods for their
manufacture.
EXAMPLE 1
3-methyl-2-(3,4,5-trimethoxybenzoyl)-isoxazolidine
a. To a solution of 26 g. (0.25 mole) of N-hydroxyurethane and 54
g. (0.25 mole) of 1,3-dibromobutane in 500 ml. of absolute ethanol,
a suspension of 35.7 g. (0.25 mole) of potassium hydroxyurethane in
100 ml. of absolute ethanol is added with stirring at 5.degree.C.
and stirring is continued for three hours at the same temperature.
Then a solution of 14 g. (0.25 mole) of potassium hydroxide in 100
ml. of absolute ethanol is added dropwise at room temperature;
stirring is continued for an hour at room temperature, and
subsequently the mixture is refluxed for 3 hours. The solid
insoluble mineral salts which form are filtered off and the
filtrate is evaporated to dryness under vacuum. The residue is
dissolved in diethyl ether, washed twice with a saturated solution
of sodium chloride and with dilute sodium hydroxide and dried over
sodium sulfate. The solution is evaporated in vacuo and the residue
is distilled under reduced pressure. 23.4 Grams of crude
2-carbethoxy-3-methyl-isoxazolidine is obtained, b.p.
110.degree.-112.degree.C./20 mm Hg.
b. A solution of 22.5 g. of the crude
2-carbethoxy-3-methyl-isoxazolidine in 370 ml. of aqueous 18%
hydrochloric acid is refluxed for 3 hours. The mixture is then
evaporated to dryness in vacuo and the residue, after dissolving in
water, is made alkaline with 150 ml. of aqueous 50 percent sodium
hydroxide. An oily product separates which is extracted with
benzene and the resulting solution is dried over potassium
carbonate. The solvent is then evaporated and the residue is
distilled under reduced pressure to give 6.65 g. of crude
3-methyl-isoxazolidine, b.p. 75.degree.-90.degree.C./100 mm Hg.
c. To a solution of 6.75 g. of the crude 3-methyl-isoxazolidine and
12 ml. (0.085 mole) of triethylamine in 135 ml. of methylene
chloride, a solution of 18 g. (0.078 mole) of
3,4,5-trimethoxybenzoyl chloride in 90 ml. of methylene chloride is
added dropwise at 5.degree.-10.degree.C. with stirring. Stirring is
continued for an hour at room temperature and 2 hours at reflux.
The reaction mixture is then washed with water, hydrochloric acid,
dilute sodium hydrogen carbonate and again with water and dried
over sodium sulfate. After evaporating the solvent, an oily residue
is obtained which is taken up with diisopropyl ether. A solid
precipitates which is filtered and recrystallized from diisopropyl
ether to give 10.8 g. of
3-methyl-2-(3,4,5-trimethoxybenzoyl)-isoxazolidine, m.p.
83.degree.-84.degree.C.
EXAMPLE 2
2-(4-acetoxy-3,5-dimethoxybenzoyl)-3-methyl-isoxazolidine
The titular compound is prepared following substantially the same
procedure described in Example 1, starting with
3-methyl-isoxazolidine and 4-acetoxy-3,5-dimethoxybenzoyl chloride.
Yield 56.4 percent, m.p. 87.degree.-89.degree.C.
EXAMPLE 3
4-ethyl-2-(3,4,5-trimethoxybenzoyl)-isoxazolidine
a. To a solution of sodium hydroxyurethane, prepared by adding at
room temperature 34.7 g. (1.15 mole) of an 80 percent oily
suspension of sodium hydride to 225 g. (2.14 mole) of
N-hydroxyurethane dissolved in 2,600 ml. of anhydrous
dimethylformamide, a solution of 226 g. (1.15 mole) of
2-ethyl-1,3-dibromopropane in 600 ml. of anhydrous
dimethylformamide is added dropwise with stirring. Stirring is
continued for three hours at room temperature, and subsequently
34.7 g. (1.15 mole) of an 80% oily suspension of sodium hydride is
added, maintaining the temperature at about 15.degree.-20.degree.C.
Stirring is continued for 20 hours at room temperature, then the
dimethylformamide is distilled off at 50.degree.C. in vacuo and the
residue, dissolved in water, is extracted five times with diethyl
ether. The ether solutions are collected, washed with dilute sodium
hydroxide and with a saturated aqueous solution of sodium chloride,
and dried over sodium sulfate. The oily residue obtained after
evaporation of the solvent is distilled to give a crude product
which is chromatographed, using benzene and benzene-diethyl ether
mixtures as the eluents. From the benzene-diethyl ether fractions,
62.3 g. of 2-carbethoxy-4-ethylisoxazolidine is obtained, b.p.
108.degree.C./1.5 mm Hg.
b. The compound obtained under (a) is hydrolyzed following the
procedure of part (b) of Example 1, to give 4-ethyl-isoxazolidine.
Yield 62.5%, b.p. 115.degree.-117.degree.C./110-130 mm Hg.
c. The titular compound is obtained by reacting equimolecular
amounts of 4-ethyl-isoxazolidine and 3,4,5-trimethoxybenzoyl
chloride as described in part (c) of Example 1. Yield 86.5 percent,
b.p. 180.degree.-185.degree.C./0.1 mm Hg.
EXAMPLE 4
5-carbomethoxy-5-methyl-2-(3,4,5-trimethoxybenzoyl)-isoxazolidine
The titular compound is obtained by following the procedure
described in part (c) of Example 1, starting with
5-carbomethoxy-5-methyl-isoxazolidine, prepared as described by M.
Ochiai, M. Obayashi and K. Morita, Tetrahedron, 23, 2641 (1967),
and 3,4,5-trimethoxybenzoyl chloride. Yield 71 percent, b.p.
195.degree.C./0.1 mm Hg.
EXAMPLE 5
2-(4-acetoxy-3,5-dimethoxybenzoyl)-5-carbomethoxy-5-methyl-isoxazolidine
The titular compound is prepared by following the procedure
described in part (c) of Example 1, starting with
5-carbomethoxy-5-methyl-isoxazolidine and
4-acetoxy-3,5-dimethoxybenzoyl chloride. Yield 83.5%, m.p.
98.degree.-99.degree.C. (from absolute ethanol).
EXAMPLE 6
5-phenyl-2-(3,4,5-trimethoxybenzoyl)-isoxazolidine
a. To a suspension of 15.3 g. (0.107 mole) of potassium
hydroxyurethane in 100 ml. of absolute ethanol, 14.15 g. (0.051
mole) of 1-phenyl-1,3-dibromopropane is added at room temperature
with stirring. Stirring is continued for two hours at room
temperature and 2.5 hours at the boiling temperature of the
reaction mixture. The inorganic precipitate which forms is filtered
off and the filtrate is evaporated to dryness in vacuo. The residue
is dissolved in diethyl ether and, upon adding an ether solution of
hydrogen chloride, a precipitate forms which, after filtration,
gives 1.95 g. of 5-phenyl-isoxazolidine hydrochloride, m.p.
116-122.degree.C. The acidic ether mother liquors are neutralized
with aqueous 10 percent sodium hydrogen carbonate, washed with
water, dried over sodium sulfate and evaporated to dryness. The
oily residue is distilled under reduced pressure, giving 4 g. of
2-carbethoxy-5-phenyl-isoxazolidine, b.p.
115.degree.-130.degree.C./0.1 mm Hg.
b. To a solution of 3.35 g. of 2-carbethoxy-5-phenyl-isoxazolidine
in 28 ml. of absolute ethanol, a solution of 1.1 g. of potassium
hydroxide in 2.8 ml. of water is added and the mixture is allowed
to stand at room temperature for 24 hours. Then the ethanol is
evaporated in vacuo and the residue is dissolved in methylene
chloride. The resulting solution is washed with water and dried
over sodium sulfate, the solvent is evaporated off and the residue,
dissolved in a small amount of absolute ethanol, is treated with an
alcoholic solution of hydrochloric acid. Upon dilution with diethyl
ether, 1 g. of 5-phenyl-isoxazolidine hydrochloride precipitates,
m.p. 128.degree.-131.degree.C.
c. To a mixture of 1.4 g. (0.0075 mole) of 5-phenyl-isoxazolidine
hydrochloride and 2.5 ml. (0.018 mole) of triethylamine in 15 ml.
of methylene chloride, a solution of 1.75 g. (0.0075 mole) of
3,4,5-trimethoxybenzoyl chloride in 10 ml. of methylene chloride is
added dropwise with stirring. The reaction mixture is refluxed
three hours with stirring, then it is washed with dilute
hydrochloric acid, with dilute sodium hydrogen carbonate, with
water and dried over sodium sulfate. After evaporating the solvent,
the oily residue is dissolved in 40 ml. of diisopropyl ether and
the resulting solution is refluxed two hours, insoluble matter
filtered off and the solution concentrated to dryness in vacuo, to
give 2.3 g. of 5-phenyl-2-(3,4,5-trimethoxybenzoyl)-isoxazolidine
as a pure, dense, undistillable oil.
EXAMPLE 7
3-phenyl-2-(3,4,5-trimethoxybenzoyl)-isoxazolidine
a. To a solution of 14.6 g. (0.1 mole) of potassium hydroxyurethane
and 10.5 g. (0.1 mole) of N-hydroxyurethane in 100 ml. of anhydrous
dimethylformamide, a solution of 19.7 g. (0.1 mole) of
.beta.-bromomethyl-styrene dissolved in 40 ml. of anhydrous
dimethylformamide is added with stirring. Stirring is continued for
half an hour, then the solvent is evaporated in vacuo and the
residue is dissolved in diethyl ether. The obtained solution is
washed with aqueous 5 percent sodium hydroxide and with water,
dried over sodium sulfate and the solvent is evaporated off. The
residue is recrystallized from diisopropyl ether to yield 19 g. of
N-carbethoxy-0-cinnamyl-hydroxylamine, m.p. 59-61.degree.C.
b. To a saturated solution of hydrogen bromide in 750 ml. of
methylene chloride, 15.5 g. of
N-carbethoxy-0-cinnamyl-hydroxylamine dissolved in 75 ml. of
methylene chloride is added at 0.degree.C. The mixture is kept for
two hours at 0.degree.C. and allowed to stand overnight at room
temperature. Then the solvent is evaporated off to give 26.9 g. of
crude oily N-carbethoxy-0-(3-bromo-3-phenylpropyl)-hydroxylamine,
which is employed as such for the subsequent step.
c. A solution of 2.35 g. of the crude product of part (b) in 10 ml.
of dimethylformamide is added with stirring to a solution of 1.8
ml. of N-methylpiperidine dissolved in 30 ml. of dimethylformamide.
Stirring is continued for 2 hours at room temperature and for two
hours at 50.degree.C. Then the mixture is poured into 160 ml. of
water, extracted three times with diethyl ether and the ether
solutions are collected and washed with dilute hydrochloric acid,
dilute sodium hydrogen carbonate and water, and dried over sodium
sulfate. The solvent is evaporated in vacuo and the residue is
distilled under reduced pressure to give 0.46 g. of
2-carbethoxy-3-phenyl-isoxazolidine, b.p. 115.degree.C./0.2 mm
Hg.
d. Following substantially the same procedure described in part (b)
of Example 6 and starting with 0.81 g. of
2-carbethoxy-3-phenyl-isoxazolidine, 0.12 g. of
3-phenyl-isoxazolidine hydrochloride is obtained, m.p.
147-150.degree.C. (from a mixture of absolute ethanol and diethyl
ether).
e. By substantially the same procedure described under part (c) of
Example 6, starting with 3-phenyl-isoxazolidine hydrochloride and
3,4,5-trimethoxybenzoyl chloride, 0.12 g. of
3-phenyl-2-(3,4,5-trimethoxybenzoyl)-isoxazolidine is obtained,
m.p. 91-93.degree.C. (from diisopropyl ether).
The compounds of the invention proved active on the central nervous
system, said activity being essentially characterized by
long-lasting hypnotic, sedative and myorelaxing effects. These
compounds display also a strong anxiety relieving effect. These
properties were evaluated after administrations to mice and rats of
effective amounts of the compounds. An impairment of motor
coordination and righting reflex after such administrations was
taken as a measure of the hypnotic effect, whereas a decreasing of
the spontaneous activity was related to the sedative properties.
The myorelaxing activity was evaluated by considering the muscular
tone, and the anxiety relieving effect was measured on the basis of
the secondary conditioned avoidance response. In representative
experiments, amounts from about 20 to about 50 mg/kg i.p. of
compounds of Examples 1, 3, 5, 6 and 7 were found to be active on
the above mentioned parameters. Moreover, these favorable
biological characteristics are generally coupled with a very low
toxicity since the LD.sub.50 values in mice are higher than 600
mg/kg i.p.
* * * * *